The present invention is directed to methods of treatment utilizing harmaceutical compositions comprising epibatidine and/or synthetic derivatives thereof, wherein the utility of the composition is based upon the fact that the active ingredients have been found to be nicotine receptor agonists. Epibatidine has the following structure: ##STR2##
Epibatidine was first isolated by Daly et al. from skins of the Ecuadoran poison frog, Epipedobates tricolor (Daly, et al., J. Am. Chem. Soc., 102: 830 (1980)). Its structure was determined by mass spectroscopy, infra red spectroscopy, and nuclear magnetic resonance as exo-2(6-chloro-3-pyridyl)-7-azabicyclo [2.2.1] heptane (1) (Spande, et al., J. Am. Chem. Soc., 114: 3475 (1992)). This alkaloid has been shown to be a potent analgesic with a nonopioid mechanism of action. The analgesic effect of epibatidine was approximately 200-times higher than morphine using hot plate assay, and approximately 500-fold that of morphine in eliciting the Straub-tail response. The epibatidine-induced analgesia was not blocked by the opioid receptor antagonist naloxone. Furthermore, it has been determined that epibatidine had a negligible affinity for opioid receptor (1/8000 times that of morphine). See, Spande, et al., J. Am. Chem. Soc., 114: 3475 (1992). The mechanism of epibatidine-induced analgesia is unknown.
The present inventors have discovered that epibatidine and synthetic analogs thereof (see, Fei and Shen, Tet. Let., 34: 4477 (1993); Fletcher, et al., J. Chem. Soc. Chem. Comm., p. 1216 (1993) and Broka, Tet. Let., 34:3251(1993)), possess another unique and unexpected utility, one which presents the ability to treat or ameliorate disease states or conditions, not commonly associated with analgesia. Thus, the present invention is directed to methods of treatment based upon the use of epibatidine and its analogs as nicotine receptor agonists.
The present invention demonstrates that epibatidine is the third natural alkaloid nicotinic receptor agonist. The other two natural alkaloids are nicotine, first isolated from leaves of tobacco in 1828, and lobeline, first isolated from Lobelia inflata (India tobacco) in 1915. See, Taylor, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 18th Ed., Gilman et al., eds., Pergamon Press, pp. 166-186 (1990).
Nicotine is a central nervous system (CNS) and ganglionic nicotinic receptor agonist and has been found to exert a potent analgesia on thermal stimuli as measured by the hot-plate or tail-flick test in both rats and mice (Tripathi, et al., J. Pharmacol. Exp. Therap, 221: 91 (1982); Sahley et al., Psychopharmacology, 65: 279 (1979); Cooley, et al., Pharmacol. Biochem. Behav., 36: 413 (1990); Christensen, et al., J. Neural. Transm. GenSec., 80: 189 (1990)).